Glucocorticoid-induced TNFR-related protein (GITR; also AITR, TNFRSF18, or CD357), a member of the TNFR superfamily, is expressed in many components of the innate and adaptive immune system and stimulates both acquired and innate immunity (Nocentini G et al., (1994) PNAS 94: 6216-6221; Hanabuchi S et al., (2006) Blood 107:3617-3623; Nocentini G & Riccardi C (2005) Eur J Immunol 35: 1016-1022; Nocentini G et al., (2007) Eur J Immunol 37: 1165-1169). It is expressed in several cells and tissues, including T, B, dendritic (DC) and Natural Killer (NK) cells and is activated by its ligand, GITR-L, mainly expressed on Antigen Presenting Cells (APCs), on endothelial cells, and also in tumor cells.
The GITR-GITRL system participates in the development of autoimmune/inflammatory responses and potentiates response to infection and tumors. For example, treating animals with GITR-Fc fusion protein ameliorates autoimmune/inflammatory diseases while GITR triggering is effective in treating viral, bacterial, and parasitic infections, as well in boosting immune response against tumors (Nocentini G et al., (2012) Br J Pharmacol 165: 2089-99). These effects are due to several concurrent mechanisms including: co-activation of effector T-cells, inhibition of regulatory T (Treg) cells, modulation of NK and dendritic cell function, activation of macrophages, and regulation of the extravasation process. The membrane expression of GITR is increased following T cell activation (Hanabuchi S et al, (2006) supra; Nocentini G & Riccardi C supra). Its triggering coactivates effector T lymphocytes (McHugh R S et al, (2002) Immunity 16: 311-323; Shimizu J et al, (2002) Nat Immunol 3: 135-142; Roncheti S et al, (2004) Eur J Immunol 34: 613-622; Tone M et al, (2003) PNAS 100: 15059-15064). GITR activation increases resistance to tumors and viral infections, is involved in autoimmune/inflammatory processes and regulates leukocyte extravasation (Nocentini G & Riccardi C (2005) supra; Cuzzocrea S et al, (2004) J Leukoc Biol 76: 933-940; Shevach E M & Stephens G L (2006) Nat Rev Immunol 6: 613-618; Cuzzocrea S et al, (2006) J Immunol 177: 631-641; Cuzzocrea S et al, (2007) FASEB J 21: 117-129).
Human GITR is expressed at very low levels in peripheral (non-activated) T cells. After T cell activation, GITR is strongly up-regulated for several days in both CD4+ and CD8+ cells (Kwon B et al, (1999) J Biol Chem 274: 6056-6061; Gurney A L et al, (1999) Curr Biol 9: 215-218; Ronchetti S et al, (2004) supra; Shimizu J et al, (2002) supra; Ji H B et al, (2004) supra; Ronchetti S et al, (2002) Blood 100: 350-352; Li Z et al, (2003) J Autoimmun 21: 83-92), with CD4+ cells having a higher GITR expression than CD8+ cells (Kober J et al, (2008) Eur J Immunol 38(10): 2678-88; Bianchini R et al, (2011) Eur J Immunol 41(8): 2269-78).
The role of human GITR in modulating immune responses indicates that it may be a suitable target for antibody-based therapy against diseases such as cancer. Antibodies against GITR are described (e.g. in WO200610502, WO2011028683, WO2015031667, WO20150353637, WO2015187835, WO2015184099, U.S. Pat. Nos. 9,255,151 and 9,255,152), but there is an ongoing need for novel agents and methods for modulating GITR activity against diseases, such as cancer.